Paroxetine (PRX), (−)-trans-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl) piperidine; (3S, 4R)-3-[5-(1,3-dioxaindanyl)oxymethyl]-4-(p-fluorophenyl)piperidine, is a 5-hydroxytryptamine (5-HT, serotonin) re-uptake inhibitor and is useful as a therapeutic agent for various diseases, including, inter alia, depression, Parkinson's disease, anxiety disorders, obsessive-compulsive disorders, panic disorder, post-traumatic stress disorder, and pre-menstrual syndrome (PMS). Paroxetine has formula (I): 
Example 2 of U.S. Pat. No. 4,007,196 discloses formation of paroxetine by demethylation of N-methylparoxetine (Me-PRX) having formula (II): 
In the process disclosed in the '196 patent, Me-PRX is demethylated by reaction with phenylchloroformate in methylene chloride to form the corresponding phenyl carbamate intermediate. The phenyl carbamate intermediate is hydrolyzed to yield paroxetine by refluxing in benzene with potassium hydroxide and methyl cellosolve for four hours. Among the disadvantages of this process are the low conversion of Me-PRX to the phenyl carbamate, resulting in low yields of paroxetine. This process also results in large quantities of phenol as an undesirable by-product.
U.S. Pat. No. 4,721,723 describes a process for preparing paroxetine wherein Me-PRX is reacted with α-chloroethyl-chloroformate (1-chloroethyl-chloroformate) to form the corresponding 1-chloroethyl carbamate of paroxetine, which is then hydrolyzed under acidic conditions to yield paroxetine. A significant disadvantage of this process is the long time required for the conversion of Me-PRX to paroxetine under the conditions disclosed in, for example, Examples 6 and 7 of the '723 patent.
EP 0 810 225 A1 discloses a process for producing paroxetine by reacting Me-PRX with a lower alkyl, lower cycloalkyl, aralkyl or CmF2m+1 ester of haloformic acid to yield a carbamate intermediate. The corresponding carbamate intermediate is hydrolyzed in an appropriate solvent under alkaline conditions to yield paroxetine, which is extracted from the reaction mixture with an appropriate solvent such as toluene. The hydrolysis of the carbamate intermediate took from 2-3 days of reflux with alkali and produced low to moderate yields of paroxetine.
WO 00/78753 discloses forming a finely divided complex of a base (preferably potassium hydroxide), and a carbamate intermediate obtained from the demethylation of Me-PRX and refluxing in a solvent (preferably toluene) to yield paroxetine.
In view of the foregoing, a need exists in the art for a high yield and time-efficient process for the preparation of paroxetine, which does not result in harmful by-products. In particular, there exists the need for such an improved process for preparing paroxetine by demethylation of N-methylparoxetine.